Molecular hybrid positron emission tomography/computed tomography imaging of cardiac angiotensin ii type 1 receptors

Kenji Fukushima, Paco E. Bravo, Takahiro Higuchi, Karl H. Schuleri, Xiaoping Lin, M. Roselle Abraham, Jinsong Xia, William B. Mathews, Robert F. Dannals, Albert C. Lardo, Zsolt Szabo, Frank M. Bengel

Research output: Contribution to journalArticle

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Abstract

Objectives: The goal of this study was to explore the feasibility of targeted imaging of the angiotensin II type 1 receptor (AT1R) in cardiac tissue, using clinical hybrid positron emission tomography/computed tomography (PET/CT). Background: AT1R is an attractive imaging target due to its key role in various cardiac pathologies, including post-infarct left ventricular remodeling. Methods: Using the novel AT1R ligand [11C]-KR31173, dynamic PET/CT was performed in young farm pigs under healthy conditions (n = 4) and 3 to 4 weeks after experimental myocardial infarction (n = 5). Ex vivo validation was carried out by immunohistochemistry and polymerase chain reaction. First-in-man application was performed in 4 healthy volunteers at baseline and under AT1R blocking. Results: In healthy pigs, myocardial KR31173 retention was detectable, regionally homogeneous, and specific for AT1R, as confirmed by blocking experiments. Metabolism in plasma was low (85 ± 2% of intact tracer after 60 min). After myocardial infarction, KR31173 retention, corrected for regional perfusion, revealed AT1R up-regulation in the infarct area relative to remote myocardium, whereas retention was elevated in both regions when compared with myocardium of healthy controls (8.7 ± 0.8% and 7.1 ± 0.3%/min vs. 5.8 ± 0.4%/min for infarct and remote, respectively, vs. healthy controls; p < 0.01 each). Postmortem analysis confirmed AT1R up-regulation in remote and infarct tissue. First-in-man application was safe, and showed detectable and specific myocardial KR31173 retention, albeit at a lower level than pigs (left ventricular average retention: 1.2 ± 0.1%/min vs. 4.4 ± 1.2%/min for humans vs. pigs; p = 0.04). Conclusions: Noninvasive imaging of cardiac AT1R expression is feasible using clinical PET/CT technology. Results provide a rationale for broader clinical testing of AT1R-targeted molecular imaging.

Original languageEnglish
Pages (from-to)2527-2534
Number of pages8
JournalJournal of the American College of Cardiology
Volume60
Issue number24
DOIs
Publication statusPublished - Dec 18 2012
Externally publishedYes

Fingerprint

Angiotensin Type 1 Receptor
Swine
Myocardium
Up-Regulation
Myocardial Infarction
Positron Emission Tomography Computed Tomography
Ventricular Remodeling
Molecular Imaging
Healthy Volunteers
Perfusion
Immunohistochemistry
Pathology
Ligands
Technology
Polymerase Chain Reaction

Keywords

  • angiotensin receptor
  • molecular imaging
  • myocardial infarction
  • positron emission tomography
  • renin-angiotensin system

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Molecular hybrid positron emission tomography/computed tomography imaging of cardiac angiotensin ii type 1 receptors. / Fukushima, Kenji; Bravo, Paco E.; Higuchi, Takahiro; Schuleri, Karl H.; Lin, Xiaoping; Abraham, M. Roselle; Xia, Jinsong; Mathews, William B.; Dannals, Robert F.; Lardo, Albert C.; Szabo, Zsolt; Bengel, Frank M.

In: Journal of the American College of Cardiology, Vol. 60, No. 24, 18.12.2012, p. 2527-2534.

Research output: Contribution to journalArticle

Fukushima, K, Bravo, PE, Higuchi, T, Schuleri, KH, Lin, X, Abraham, MR, Xia, J, Mathews, WB, Dannals, RF, Lardo, AC, Szabo, Z & Bengel, FM 2012, 'Molecular hybrid positron emission tomography/computed tomography imaging of cardiac angiotensin ii type 1 receptors', Journal of the American College of Cardiology, vol. 60, no. 24, pp. 2527-2534. https://doi.org/10.1016/j.jacc.2012.09.023
Fukushima, Kenji ; Bravo, Paco E. ; Higuchi, Takahiro ; Schuleri, Karl H. ; Lin, Xiaoping ; Abraham, M. Roselle ; Xia, Jinsong ; Mathews, William B. ; Dannals, Robert F. ; Lardo, Albert C. ; Szabo, Zsolt ; Bengel, Frank M. / Molecular hybrid positron emission tomography/computed tomography imaging of cardiac angiotensin ii type 1 receptors. In: Journal of the American College of Cardiology. 2012 ; Vol. 60, No. 24. pp. 2527-2534.
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abstract = "Objectives: The goal of this study was to explore the feasibility of targeted imaging of the angiotensin II type 1 receptor (AT1R) in cardiac tissue, using clinical hybrid positron emission tomography/computed tomography (PET/CT). Background: AT1R is an attractive imaging target due to its key role in various cardiac pathologies, including post-infarct left ventricular remodeling. Methods: Using the novel AT1R ligand [11C]-KR31173, dynamic PET/CT was performed in young farm pigs under healthy conditions (n = 4) and 3 to 4 weeks after experimental myocardial infarction (n = 5). Ex vivo validation was carried out by immunohistochemistry and polymerase chain reaction. First-in-man application was performed in 4 healthy volunteers at baseline and under AT1R blocking. Results: In healthy pigs, myocardial KR31173 retention was detectable, regionally homogeneous, and specific for AT1R, as confirmed by blocking experiments. Metabolism in plasma was low (85 ± 2{\%} of intact tracer after 60 min). After myocardial infarction, KR31173 retention, corrected for regional perfusion, revealed AT1R up-regulation in the infarct area relative to remote myocardium, whereas retention was elevated in both regions when compared with myocardium of healthy controls (8.7 ± 0.8{\%} and 7.1 ± 0.3{\%}/min vs. 5.8 ± 0.4{\%}/min for infarct and remote, respectively, vs. healthy controls; p < 0.01 each). Postmortem analysis confirmed AT1R up-regulation in remote and infarct tissue. First-in-man application was safe, and showed detectable and specific myocardial KR31173 retention, albeit at a lower level than pigs (left ventricular average retention: 1.2 ± 0.1{\%}/min vs. 4.4 ± 1.2{\%}/min for humans vs. pigs; p = 0.04). Conclusions: Noninvasive imaging of cardiac AT1R expression is feasible using clinical PET/CT technology. Results provide a rationale for broader clinical testing of AT1R-targeted molecular imaging.",
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author = "Kenji Fukushima and Bravo, {Paco E.} and Takahiro Higuchi and Schuleri, {Karl H.} and Xiaoping Lin and Abraham, {M. Roselle} and Jinsong Xia and Mathews, {William B.} and Dannals, {Robert F.} and Lardo, {Albert C.} and Zsolt Szabo and Bengel, {Frank M.}",
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AU - Bravo, Paco E.

AU - Higuchi, Takahiro

AU - Schuleri, Karl H.

AU - Lin, Xiaoping

AU - Abraham, M. Roselle

AU - Xia, Jinsong

AU - Mathews, William B.

AU - Dannals, Robert F.

AU - Lardo, Albert C.

AU - Szabo, Zsolt

AU - Bengel, Frank M.

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KW - angiotensin receptor

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KW - renin-angiotensin system

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